The present invention provides a new use of taxoid derivatives. More specifically, the present invention provides a method for treating abnormal cell proliferation in the brain of mammals, including humans, by administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: 
wherein:
Z represents a hydrogen atom or a radical of formula (II): 
wherein:
R1 represents:
a benzoyl radical which is unsubstituted or substituted with at least one identical or different atom or radical selected from halogen atoms and alkyl radicals containing from 1 to 4 carbon atoms, alkoxy radicals containing from 1 to 4 carbon atoms or trifluoromethyl radicals,
a thenoyl or furoyl radical, or
a radical R2xe2x80x94Oxe2x80x94COxe2x80x94 in which R2 represents:
an alkyl radical containing from 1 to 8 carbon atoms,
an alkenyl radical containing from 2 to 8 carbon atoms,
an alkynyl radical containing from 3 to 8 carbon atoms,
a cycloalkyl radical containing from 3 to 6 carbon atoms,
a cycloalkenyl radical containing from 4 to 6 carbon atoms, or
a bicycloalkyl radical containing from 7 to 10 carbon atoms,
these radicals being optionally substituted with one or more substituents selected from halogen atoms and hydroxyl radicals, alkoxy radicals containing from 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains from 1 to 4 carbon atoms, piperidino or morpholino radicals, 1 -piperazinyl radicals, which radicals are unsubstituted or substituted at position 4 with an alkyl radical containing from 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion contains from 1 to 4 carbon atoms, cycloalkyl radicals containing from 3 to 6 carbon atoms, cycloalkenyl radicals containing from 4 to 6 carbon atoms, phenyl radicals which are unsubstituted or substituted with at least one atom or radical selected from halogen atoms and alkyl radicals containing from 1 to 4 carbon atoms or alkoxy radicals containing from 1 to 4 carbon atoms, cyano or carboxyl radicals or alkoxycarbonyl radicals in which the alkyl portion contains from 1 to 4 carbon atoms,
a phenyl or xcex1- or xcex2-naphthyl radical which is unsubstituted or substituted with at least one atom or radical selected from halogen atoms and alkyl radicals containing from 1 to 4 carbon atoms or alkoxy radicals containing from 1 to 4 carbon atoms,
a 5-membered aromatic heterocyclic radical preferably selected from furyl and thienyl radicals, or
a saturated heterocyclic radical containing from 4 to 6 carbon atoms, which is unsubstituted or substituted with at least one alkyl radical containing from 1 to 4 carbon atoms;
R3 represents:
an unbranched or branched alkyl radical containing from 1 to 8 carbon atoms,
an unbranched or branched alkenyl radical containing from 2 to 8 carbon atoms,
an unbranched or branched alkynyl radical containing from 2 to 8 carbon atoms,
a cycloalkyl radical containing from 3 to 6 carbon atoms,
a phenyl or xcex1- or xcex2-naphthyl radical which is unsubstituted or substituted with at least one atom or radical selected from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals,
or a 5-membered aromatic heterocycle containing one or more identical or different hetero atoms selected from nitrogen, oxygen and sulphur atoms, and which is unsubstituted or substituted with at least one identical or different substituent selected from halogen atoms and alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl and alkoxycarbonyl radicals,
with the provisos that, in the substituents of the phenyl, xcex1- or xcex2-naphthyl and aromatic heterocyclic radicals, the alkyl radicals and the alkyl portions of the other radicals contain from 1 to 4 carbon atoms, and that the alkenyl and alkynyl radicals contain from 2 to 8 carbon atoms, and that the aryl radicals are phenyl or xcex1- or xcex2-naphthyl radicals;
R4 represents:
an alkoxy radical containing from 1 to 6 carbon atoms in an unbranched or branched chain,
an alkenyloxy radical containing from 3 to 6 carbon atoms in an unbranched or branched chain,
an alkynyloxy radical containing from 3 to 6 carbon atoms in an unbranched or branched chain,
a cycloalkyloxy radical containing from 3 to 6 carbon atoms, or
a cycloalkenyloxy radical containing from 4 to 6 carbon atoms,
these radicals being which is unsubstituted or substituted with at least one halogen atom or with an alkoxy radical containing from 1 to 4 carbon atoms, an alkylthio radical containing from 1 to 4 carbon atoms or a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains from 1 to 4 carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl or N,N-dialkylcarbamoyl radical in which each alkyl portion contains from 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or 6-membered heterocyclic radical containing or not containing a second hetero atom selected from oxygen, sulphur, and nitrogen atoms, which is unsubstituted or substituted with an alkyl radical containing from 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl portion contains from 1 to 4 carbon atoms; and
R5 represents:
an alkoxy radical containing from 1 to 6 carbon atoms in an unbranched or branched chain,
an alkenyloxy radical containing from 3 to 6 carbon atoms,
an alkynyloxy radical containing from 3 to 6 carbon atoms,
a cycloalkyloxy radical containing from 3 to 6 carbon atoms or
a cycloalkenyloxy radical containing from 3 to 6 carbon atoms,
these radicals being which is unsubstituted or substituted with at least one halogen atom or with an alkoxy radical containing from 1 to 4 carbon atoms, an alkylthio radical containing from 2 to 4 carbon atoms or a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains from 1 to 4 carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl or N,N-dialkylcarbamoyl radical in which each alkyl portion contains from 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or 6-membered heterocyclic radical containing or not containing a second hetero atom selected from oxygen, sulphur, and nitrogen atoms, which is unsubstituted or substituted with an alkyl radical containing from 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl portion contains from 1 to 4 carbon atoms.
Both the foregoing general description and the following detailed description of the invention are exemplary and explanatory only and are not necessarily restrictive of the claimed invention.
Preferably, the aryl radicals which can be represented by R3 are phenyl or xcex1- or xcex2-naphthyl radicals which is unsubstituted or substituted with at least one atom or radical selected from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro, and trifluoromethyl radicals, with the provisos that the alkyl radicals and the alkyl portions of the other radicals contain from 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain from 2 to 8 carbon atoms, and that the aryl radicals are phenyl or xcex1- or xcex2-naphthyl radicals.
Preferably, the heterocyclic radicals which can be represented by R3 are 5-membered aromatic heterocyclic radicals containing one or more identical or different atoms selected from nitrogen, oxygen, and sulphur atoms, which is unsubstituted or substituted with at least one identical or different substituents selected from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals containing from 1 to 4 carbon atoms, aryl radicals containing from 6 to 10 carbon atoms, alkoxy radicals containing from 1 to 4 carbon atoms, aryloxy radicals containing from 6 to 10 carbon atoms, amino radicals, alkylamino radicals containing from 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains from 1 to 4 carbon atoms, acylamino radicals in which the acyl portion contains from 1 to 4 carbon atoms, alkoxycarbonylamino radicals containing from 1 to 4 carbon atoms, acyl radicals containing from 1 to 4 carbon atoms, arylcarbonyl radicals in which the aryl portion contains from 6 to 10 carbon atoms, cyano, carboxyl and carbamoyl radicals, alkylcarbamoyl radicals in which the alkyl portion contains from 1 to 4 carbon atoms, dialkylcarbamoyl radicals in which each alkyl portion contains from 1 to 4 carbon atoms, and alkoxycarbonyl radicals in which the alkoxy portion contains from 1 to 4 carbon atoms.
Preferably, the radicals R4 and R5, which may be identical or different, represent unbranched or branched alkoxy radicals containing from 1 to 6 carbon atoms, which is unsubstituted or substituted with a methoxy, ethoxy, ethylthio, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-pyrrolidinocarbonyl, or N-piperidinocarbonyl radical.
More preferably, Z represents a hydrogen atom or a radical of formula (II) in which R1 represents a benzoyl radical or a radical R2xe2x80x94Oxe2x80x94COxe2x80x94 in which R2 represents a tert-butyl radical, and R3 represents an alkyl radical containing from 1 to 6 carbon atoms, an alkenyl radical containing from 2 to 6 carbon atoms, a cycloalkyl radical containing from 3 to 6 carbon atoms, a phenyl radical which is unsubstituted or substituted with at least one identical or different atoms or radicals selected from halogen atoms(fluorine, chlorine) and alkyl(methyl), alkoxy(methoxy), dialkylamino(dimethylamino), acylamino(acetylamino), alkoxycarbonylamino(tert-butoxycarbonylamino) and trifluoromethyl radicals, and a 2- or 3-furyl, 2- or 3-thienyl, and a 2-, 4-, or 5-thiazolyl radical, and R4 and R5, which may be identical or different, each represent an unbranched or branched alkoxy radical containing from 1 to 6 carbon atoms.
Still more preferably, Z represents a hydrogen atom or a radical of general formula (II) in which R1 represents a benzoyl radical or a radical R2xe2x80x94Oxe2x80x94COxe2x80x94 in which R2 represents a tert-butyl radical, and R3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl radical, and R4 and R5, which may be identical or different, each represent a methoxy, ethoxy, or propoxy radical.
Even more preferably, R3 represents a phenyl radical, R1 represents a tert-butoxycarbonyl radical, and R4 and R5, which may be identical or different, represent a methoxy, ethoxy, or propoxy radical.
Even more preferably, the present invention relates to 4xcex1-acetoxy-2xcex1-benzoyloxy-5xcex2, 20-epoxy-1xcex2-hydroxy-7xcex2, 10xcex2-dimethoxy-9-oxo-11-taxen-13xcex1-yl (2R,3S)-3 tert -butoxycarbonylamino-2-hydroxy-3-phenylpropionate of formula (Ia): 
WO 96/30355, the entire content of which is incorporated herein by reference, discloses two processes for preparing a derivative according to the present invention. The first preparatory process is a multi-step process starting with 10-deacetylbaccatin III of formula (III): 
Compound (III) is selectively protected in positions 7 and 13, for example in the form of a silyl diether, followed by reaction with a product of formula (IV):
Rxe2x80x94Xxe2x80x83xe2x80x83(IV)
in which R represents a radical as defined above, and X represents a reactive ester residue, such as a sulphuric or sulphonic ester residue or a halogen atom, to give a product bearing the unitxe2x80x94OR in position 10 and silyl groups in positions 7 and 13. Next, the silyl protecting groups are replaced with hydrogen atoms to give a compound still bearing the group xe2x80x94OR in position 10, and bearing OH groups in positions 7 and 13. The latter derivative is etherified selectively in position 7 by reaction with the derivative of formula IV to give the derivative of formula (I) in which Z is equal to hydrogen.
The next step involves esterifying in position 13 the derivatives of formula (I), in which Z represents hydrogen, in the presence of a xcex2-lactam, according to a process which is well known to persons of skill in the art, e.g., as described in European patent EP 617,018, or in the presence of an oxazolidine, e.g., as described in patent WO 96/30355. The entire content of EP 617,018 is incorporated herein by reference. After deprotection of the protecting groups in positions 7 and 10, an ester of formula (I) is obtained in which Z is other than hydrogen and R represents hydrogen.
The next step involves reacting the positions 7 and 10 simultaneously by the action of a reagent formed in situ from a sulphoxide of formula (V) and acetic anhydride (Pummerer-type reaction):
Rxe2x80x94SOxe2x80x94Rxe2x80x83xe2x80x83(V)
in which R has the same meaning as defined above, to form a C-7 and C-10 alkylthioalkyloxy intermediate compound.
The final step, which allows the desired compound of formula (I) to be obtained, is carried out on the intermediate compound obtained above by the action of activated Raney nickel.
Generally, the action of the reagent formed in situ from sulphoxide of formula (V), preferably dimethyl sulphoxide and acetic anhydride, is carried out in the presence of acetic acid, or an acetic acid derivative such as a haloacetic acid, at a temperature ranging from 0 to 50xc2x0 C.
Generally, the action of the activated Raney nickel in the presence of an aliphatic alcohol or an ether is carried out at a temperature ranging from xe2x88x9210 to 60xc2x0 C.
Another process is described in French patent application FR 97-14442, the entire content of which is incorporated herein by reference. This process allows, in a single step, the direct, selective, and simultaneous alkylation of the two hydroxyl functions in positions 7 and 10 of 10-deacetylbaccatin, or of derivatives thereof esterified in position 13, of formula (VI): 
in which A represents hydrogen or a side chain of formula (IIa) below: 
in which G represents a protecting group for the hydroxyl function, and R1 and R3 have the same meaning as in formula (II), or an oxazolidine unit of formula (IIb): 
in which R1 and R3 have the same meaning as in formula (II), and Ra and Rb, which may be identical or different, represent hydrogen or alkyl, aryl, halo, alkoxy, arylalkyl, alkoxyaryl, haloalkyl, haloaryl, wherein the substituents may optionally form a 4- to 7-membered ring.
It is preferable to use 10-deacetylbaccatin as starting material, i.e., the product of formula (III). This allows appreciable economy in the process and moreover avoids the intermediate protection and deprotection steps necessary in the old processes.
Among the groups G for protecting the hydroxyl function of formula (IIa), it is generally preferred to choose any of the protecting groups described in texts such as Greene and Wuts, Protective Groups in Organic Synthesis, 1991, John Wiley and Sons, and MacOmie, Protective Groups in Organic Chemistry, 1975, Plenum Press, that are deprotected under conditions that degrade the rest of the molecule little or not at all, e.g.:
ethers, preferably methoxymethyl ether, 1-ethoxyethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, benzyl ethers which is unsubstituted or substituted with at least one groups such as methoxy, chloro, nitro, 1-methyl-1-methoxyethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, and silyl ethers such as trialkylsilyl ethers; or
carbonates such as trichloroethyl carbonates.
The entire content of both cited texts entitled Protective Groups in Organic Synthesis is incorporated herein by reference.
Preferably, the radicals Ra and Rb of general formula (IIb) are selected from those described in International patent publication WO 94/07878. More preferably, Ra is hydrogen and Rb is a p-methoxyphenyl radical.
The alkylating agent is selected from:
alkyl halides, preferably alkyl iodides (RI);
alkyl sulphates, such as methyl sulphate; and
oxoniums, such as trialkyloxonium boric salts, preferably trimethyloxonium
tetrafluoroborate (Me3OBF4).
Methyl iodide is preferably used.
The alkylating agent is used in the presence of an anionization agent, such as one or more strong bases, in anhydrous medium.
Examples of bases which can be used in anhydrous medium include, but are not limited to:
alkali metal hydrides, such as sodium or potassium hydride;
alkali metal alkoxides, such as potassium tert-butoxide;
silver oxide (Ag2O);
1,8-bis(dimethylamino)naphthalene; and
mono- or dimetallic base mixtures such as those described, e.g., in publications such as P. Caubxc3xa8re, Chem. Rev. (1993) 93, 2317-2334 or M. Schlosser, Mod. Synth. Methods (1992) 6, 227-271, the entire content of both publications being incorporated herein by reference; preferably, the alkyllithium/alkali metal t-butoxide or alkali metal amide/alkali metal t-butoxide combinations. One of the two bases can be generated in situ.
The combination of alkylating agent and anionization agent is preferably methyl iodide and potassium hydride.
The reaction is preferably carried out in an organic medium that is inert under the reaction conditions. Among the solvents, it is preferable to use:
ethers such as tetrahydrofuran or dimethoxyethane;
when silver oxide is used, it is preferred to use polar aprotic solvents, e.g., dimethylformamide, or aromatic solvents, e.g., toluene; and
when 1,8-bis(dimethylamino)naphthatene is used, it is preferred to use alkylesters such as ethylacetate.
Preferably, the molar ratio between the anionization agent and the substrate is greater than 2, and more preferably ranges from 2 and 20.
Preferably, the molar ratio between the alkylating agent and the substrate is greater than 2, and more preferably ranges from about 2 to about 40.
Preferably, the reaction temperature ranges from about xe2x88x9230xc2x0 C. to about 80xc2x0 C.
Preferably, the reaction time ranges from a few hours to about 48 hours, depending on the reagents chosen.
After the alkylating step, when the latter is carried out on 10-deacetylbaccatin, the process then proceeds to the esterification step in a known manner, according, e.g., to the processes described in EP 617,018 or WO 96/30355.
Thus, according to a first 3-step process, the procedure begins with the dialkylation of 10-deacetylbaccatin using an alkylating agent in the presence of a strong base. In a second step, the 10-deacetylbaccatin dietherified in positions 7 and 10 is coupled in position 13 with a suitably protected xcex2-lactam in the presence of an activating agent selected from tertiary amines and metal bases which ensure the formation of an alkoxide in position 13. Deprotection of the side chain is then achieved by the action of an inorganic or organic acid.
According to a second 3-step process, the procedure first begins with the dialkylation of 10-deacetylbaccatin, using an alkylating agent in the presence of a strong base. In a second step, the 10-deacetylbaccatin dietherified in positions 7 and 10 is coupled, in position 13, with an oxazolidine in the presence of a coupling agent such as diimides in the presence of an activating agent such as dialkylaminopyridines. Opening of the oxazolidine is achieved by the action of an inorganic or organic acid.
According to a third process, the procedure begins with the esterification in position 13 of baccatin, suitably protected in positions 7 and 10, with a xcex2-lactam or an oxazolidine in the presence of a coupling agent and/or an activating agent as described in the above two processes. After deprotection in positions 7 and 10, the dietherification in positions 7 and 10 is carried out by an alkylating agent in the presence of a strong base. Deprotection of the side chain is then achieved by the action of an inorganic or organic acid.
The products of general formula (I) have remarkable biological properties.
In vitro, measurement of the biological activity was carried out on tubulin extracted from pig brain by the method of M. L. Shelanski et al., Proc. Natl. Acad. Sci. USA, 70, 765-768 (1973). Study of the depolymerization of the microtubules into tubulin was carried out according to the method of G. Chauvixc3xa8re et al., C. R. Acad. Sci., 293, sxc3xa9rie II, 501-503 (1981). The entire content of the preceding two articles is incorporated herein by reference.
In vivo, the products of general formula (I) proved active in mice grafted with the B16 melanoma at doses of between 1 and 50 mg/kg intraperitoneally, as well as on other liquid or solid tumors.
The compounds of formula (I) have anti-tumor properties, more particularly, activity against tumors which are resistant to Taxol(copyright) and Taxotere(copyright). Such tumors include, for example, brain tumors which have an elevated expression of mdr 1 gene (multi-drug resistant gene).
Multi-drug resistance is the resistance by a tumor against various compounds having differing structures and mechanisms of action. Taxoids are generally known to be highly recognized by experimental tumors such as P388/DOX, a P388 murine leukemia cell line selected for doxorubicin (DOX) resistance, which express mdr 1. The compounds of formula (I) according to the present invention are less recognized by P388/DOX. More particularly, the compounds are less recognized than Taxotere(copyright) by mdr 1.
The compounds of formula (I) are mainly used for preparing a medicine for treating abnormal cell proliferation in the brain.
The compound, preferably the compound of formula (I) where R4 and R5 are each methoxy, has the ability to cross the blood brain barrier. It is active compared to the other known taxoids such as Taxol(copyright) or Taxotere(copyright) for treating brain cancer.
The product of formula (I) can be used concurrently with at least one other therapeutic treatment. It is preferably used with other therapeutic treatments including, but not limited to, antineoplastic drugs, monoclonal antibodies, immunotherapies, radiotherapies, or biological response modifiers. Examples of biological response modifiers include, but are not limited to, lymphokines and cytokines, interleukins, xcex1, xcex2, or xcex4 interfeons, and TNF.
The product of formula (I) is preferably administered by parenteral administration, including, but not limited to, intravenous, intraperitoneal, intramuscular, and subcutaneous administration.